Phase II Study to Analyze Sarilumab in Non-Infectious Uveitis
- Conditions
- Uveitis
- Interventions
- Drug: Folic/folinic acidOther: Placebo (for Sarilumab)
- Registration Number
- NCT01900431
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objective:
To evaluate the efficacy of sarilumab at Week 16 in participants with non-infectious uveitis (NIU).
Secondary Objectives:
To evaluate the change in best corrected visual acuity (BCVA). To evaluate the safety of subcutaneous sarilumab in participants with NIU. To evaluate the change in macular edema. To evaluate the change in other signs of ocular inflammation. To evaluate the effect on retinal vessel leakage. To evaluate the effect of sarilumab on reducing concomitant immunosuppressant therapy.
To evaluate the change in ocular inflammation in the anterior chamber. To evaluate the pharmacokinetics of sarilumab in NIU participants. To evaluate the immunogenicity with anti-drug antibodies (ADA).
- Detailed Description
The total duration per participant was up to 58 weeks, which included a 2 week screening period, 16 weeks principal treatment period (Part A), 34 weeks extension treatment period (Part B) or open label treatment period (Part C), and 6 weeks after last treatment administration.
Participants with decrease in vitreous haze (VH) ≥2; or corticosteroids dose \<10 mg/day at Week 16 were considered as responders. Participants who did not complete the principal treatment period (Part A) due to lack of efficacy; or no decrease in VH ≥2 and corticosteroids dose ≥10 mg/day at Week 16; or no decrease in VH ≥2 and corticosteroids dose missing at Week 16; or non-responder according to medical review, were considered as non-responders.
Responder participants, observed at Week 16 (at the end of Part A), were invited to continue in the extension treatment period (Part B).
Non-responder participants, observed within the first 16 weeks, were offered to be treated by open-label sarilumab (Part C).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 58
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Sarilumab Placebo (for Sarilumab) subcutaneous (SC) injection every 2 weeks (q2w) for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with Methotrexate (MTX) 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Sarilumab 200 mg q2w Sarilumab Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Placebo Prednisone Placebo (for Sarilumab) subcutaneous (SC) injection every 2 weeks (q2w) for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with Methotrexate (MTX) 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Placebo Methotrexate Placebo (for Sarilumab) subcutaneous (SC) injection every 2 weeks (q2w) for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with Methotrexate (MTX) 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Placebo Folic/folinic acid Placebo (for Sarilumab) subcutaneous (SC) injection every 2 weeks (q2w) for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with Methotrexate (MTX) 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Placebo Placebo (for Sarilumab) Placebo (for Sarilumab) subcutaneous (SC) injection every 2 weeks (q2w) for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with Methotrexate (MTX) 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Sarilumab 200 mg q2w Folic/folinic acid Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Sarilumab 200 mg q2w Methotrexate Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C). Sarilumab 200 mg q2w Prednisone Sarilumab 200 mg SC injection q2w for 16 weeks during principal treatment period (Part A) with background therapy of Prednisone (or equivalent oral corticosteroid) ≥15 mg/day and \<80 mg/day as single therapy or in combination with MTX 10 to 25 mg/week and folic acid per local prescribing practice. Responders continued with the same treatment regimen up to Week 50 during extension treatment period (Part B) and non-responders were proposed to be treated with open-label Sarilumab 200 mg q2w in open-label treatment period (Part-C).
- Primary Outcome Measures
Name Time Method Percentage of Participants With at Least 2-step Reduction in Vitreous Haze (VH) or Prednisone Dose <10 mg/Day at Week 16 Week 16 At least 2-step reduction in VH per central review from baseline was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 \[low opacity\] to 8 \[more opacity\]) images (in increasing order of opacity) are equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Participants with prednisone dose \<10 mg/day (or equivalent oral corticosteroid) were also evaluated.
- Secondary Outcome Measures
Name Time Method Change From Baseline in VH Scale at Week 16 Baseline to Week 16 Change from baseline in VH scale was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 \[low opacity\] to 8 \[more opacity\]) images (in increasing order of opacity) were equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Least squares (LS) mean was calculated using mixed model for repeated measurements (MMRM) model with treatment groups, visits and visit-by-treatment groups interaction as fixed categorical effects as well as fixed continuous covariate of baseline adjudicated VH.
Percent Change From Baseline in CRT at Week 16 Baseline to Week 16 CRT was measured by SD-OCT, a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (\<4, \>=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT.
Percentage of Participants With Anterior Chamber (AC) Cell Score = 0 or At Least 2-step Reduction in Score at Week 16 Week 16 Participants with AC cell score = 0 or with ≥2 step reduction from baseline at Week 16 were evaluated. Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: grade 0 = no cells; grade +0.5 = 1 - 5 cells; grade +1 = 6 - 25 cells; grade +2= 26 - 50 cells; grade +3 = too many to count.
Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Week 16 Baseline to Week 16 BCVA score is based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters, and then at 1 meter. The range of ETDRS is 0 to 100 letters. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (\<4, \>=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline BCVA.
Change From Baseline in Central Retinal Thickness (CRT) At Week 16 Baseline to Week 16 CRT was measured by spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. All images were transmitted to the central reading center. SD-OCT was performed in the study eye after pupil dilation. LS mean was calculated using MMRM model with treatment groups, randomization strata of VH level (\<4, \>=4), visits and visit-by-treatment groups interaction as fixed categorical effects, as well as, fixed continuous covariate of baseline CRT.
Percentage of Participants With CRT Thickness <300 Microns at Week 16 Week 16 Pharmacokinetics (PK) Assessment: Serum Functional Sarilumab Concentration Predose on Day 1 (Baseline), Week 2, 4, 8, 12, 16, 24, 36, 52, and end of study (EOS) (Week 56) Serum functional (unbound) sarilumab concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) method with a lower limit of quantification (LLOQ) of 294 ng/mL. Concentrations below LLOQ were set to zero for samples at predose. Post-treatment concentrations below LLOQ were replaced by LLOQ/2. The samples were considered non-eligible for the analysis if the previous dosing time was \<11 days or \>17 days before the sampling time for every other week regimens.
Percentage of Participants Without Retinal Vessel Leakage on Fluorescein Angiography (FA) at Week 16 Week 16 Percentage of Participants With Prednisone Dose of ≤5 mg/Day (or Equivalent Oral Corticosteroid) at Week 16 Week 16 Participants with prednisone dose ≤5 mg/day (or equivalent oral corticosteroid) at Week 16 were evaluated.
Trial Locations
- Locations (20)
Investigational Site Number 840007
🇺🇸Cleveland, Ohio, United States
Investigational Site Number 792004
🇹🇷Izmir, Turkey
Investigational Site Number 792006
🇹🇷Izmir, Turkey
Investigational Site Number 250002
🇫🇷Paris, France
Investigational Site Number 840008
🇺🇸Worcester, Massachusetts, United States
Investigational Site Number 792005
🇹🇷Ankara, Turkey
Investigational Site Number 792001
🇹🇷Ankara, Turkey
Investigational Site Number 724001
🇪🇸Barcelona, Spain
Investigational Site Number 203002
🇨🇿Praha 2, Czechia
Investigational Site Number 250001
🇫🇷Paris, France
Investigational Site Number 724003
🇪🇸Barcelona, Spain
Investigational Site Number 792002
🇹🇷Istanbul, Turkey
Investigational Site Number 792003
🇹🇷Istanbul, Turkey
Investigational Site Number 840005
🇺🇸Slingerlands, New York, United States
Investigational Site Number 840009
🇺🇸Omaha, Nebraska, United States
Investigational Site Number 203001
🇨🇿Brno, Czechia
Investigational Site Number 840006
🇺🇸Arlington, Texas, United States
Investigational Site Number 380001
🇮🇹Milano, Italy
Investigational Site Number 380003
🇮🇹Padova, Italy
Investigational Site Number 380004
🇮🇹Reggio Emilia, Italy